This invention relates to sulfonamide and carboamide derivatives. More particularly, this invention relates to
(1) the compounds of the formula (I): 
(wherein all symbols are as hereinafter defined.),
(2) processes for preparing them and
(3) Prostaglandin E2 (abbreviated as PGE2) antagonists or agonists which comprise them as an active ingredient.
PGE2 has been known as metabolite in the arachidonate cascade. It has been known that PGE2 causes uterine contraction, induction of pain, promotion of digestive peristalsis, awakening effect, vesica contraction, suppression of gastric acid secretion or reduction of blood pressure etc. The PGE2 antagonist or PGE2 agonist is expected to show the following actions.
To antagonize against PGE2 means to suppress the effects above mentioned, so such an activity is linked to inhibition of uterine contraction, analgesic action, inhibition of digestive peristalsis, induction of sleep or increase of vesical capacity. Therefore, PGE2 antagonists are considered to be useful for the prevention of abortion, as analgesics, as antidiarrheals, as sleep inducers or as agents for treating pollakiuria.
To show PGE2 agonistic activity means to promote the effects above mentioned, so such an activity is linked to uterine contraction, promotion of digestive peristalsis, suppression of gastric acid secretion or reduction of blood pressure or diuresis. Therefore, PGE2 agonists are considered to be useful as abortifacient, cathartic, antiulcer, anti-gastritis, antihypertensive or diuretic agents.
A lot of PGE2 agonists including PGE2 itself etc. have been known, but only a few compounds (PGE2 antagonists) possessing the inhibition of activity of PGE2 by antagonizing against PGE2 have been known.
For example, the patent applications relating to PGE antagonists are as follows:
In the specification of WO-96/03380, it is disclosed that the compounds of the formula (A): 
(wherein A is phenyl which may be substituted etc., B is ring system which may be substituted, D is ring system which may be substituted, R1A is carboxyl etc., R2A is H, C1-6 alkyl etc., R3A is H, C1-4 alkyl, R4A is H, C1-4 alkyl (as excerpt).) are active as PGE antagonists.
In the specification of WO-96/06822, it is disclosed that the compounds of the formula (B): 
(wherein A is ring system which may be substituted, B is hetero aryl ring which may be substituted or phenyl which may be substituted, D is ring system which may be substituted, XB is (CHR4B)nB or (CHR4B)pCR4Bxe2x95x90CR4B(CHR4B)q, R1B is carboxyl etc., R3B is H, C1-4 alkyl, R4B is H, C1-4 alkyl (as excerpt)) are active PGE antagonists.
In the specification of WO-96/11902, it is disclosed that the compounds of the formula (C): 
(wherein A, B and D are various ring systems, R1C is carboxyl etc., R3C is H, C1-4 alkyl. Z is xe2x80x94(CH(R5C))m etc. (as excerpt)) are active as PGE antagonists.
On the other hand, some compounds having a similar structure to the present invention compounds have been known.
For example, the following compound is described in Justus Liebigs Ann. Chem. (1909), 367, 133: 
(wherein RD is H or ethyl.)
The following compound is described in Khim. Geterotsikl. Soedin (1974), (6), 760: 
(wherein RE is phenethyl, benzyl, hexadecyl, decyl, nonyl, butyl, propyl, ethyl, methyl.)
The following compound is described in Khim. Geterotsikl. Soedin (1972), (10), 1341: 
(wherein RF is nitro or methoxy.)
The following compound is described in Khim. Geterotsikl. Soedin (1972), (5), 616: 
The following compound is described in Khim. Geterotsikl. Soedin (1976), (5), 641: 
The following compound is described in Khim. Geterotsikl. Soedin (1971), (7), 1028: 
The following compound is described in Khim. Geterotsikl. Soedin (1970), (12), 1597: 
(wherein each RK is Br or Cl.)
The compounds of the formula (A), (B) and (C) in the related arts possess the same pharmacological activity as the present invention compounds. But there is a difference in structure as follows: The present invention compounds have sulfonamide or carboamide as an essential element in their structure. On the other hand, the compounds described in such related arts have ether or alkylene in the corresponding part. So, it is not easy to predict the present invention compounds from the structure of these related arts.
In addition, the compounds of the formula (D) to (K) relate to the study for synthesis only. In these literature, there is no description on pharmacological activity. The carboxyl group in such compounds is connected at the ortho position, so the present invention compounds are different from such compounds in structure. Therefore, it is not easy to predict the present invention from such compounds possessing the different activity and structure.
The present invention relates to
(1) sulfonamide or carboamide derivatives of the formula (I) 
(wherein 
each, independently, is C5-15 carbocyclic ring or 5-7 membered heterocyclic ring containing one or two oxygen, sulfur or nitrogen atom(s),
Z1 is
xe2x80x94COR1,
xe2x80x94C1-4 alkylene-COR1,
xe2x80x94CHxe2x95x90CHxe2x80x94COR1,
xe2x80x94Cxe2x89xa1COR1, or
xe2x80x94Oxe2x80x94C1-3 alkylene-COR1 
(wherein R1 is hydroxy, C1-4 alkoxy or formula
NR6R7
(wherein R6 and R7 each, independently, is H or C1-4 alkyl.).), or xe2x80x94C1-5 alkylene-OH,
Z2 is H, C1-4 alkyl, C1-4 alkoxy, nitro, halogen, trifluoromethyl, trifluoromethoxy, hydroxy or COR1 (wherein R1 is as hereinbefore defined.),
Z3 is single bond or C1-4 alkylene,
Z4 is SO2 or CO,
Z5 is
(1) C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl,
(2) phenyl, C3-7 cycloalkyl, or 5-7 membered heterocyclic ring containing one or two oxygen, sulfur or nitrogen atom(s), or
(3) C1-4 alkyl, C2-4 alkenyl or C2-4 alkynyl substituted by phenyl or C3-7 cycloalkyl
(phenyl, C3-7 cycloalkyl, and 5-7 membered heterocyclic ring containing one or two oxygen, sulfur or nitrogen atom(s) mentioned in the above (2) and (3) may be substituted by 1-5 of R5 (wherein R5 (if two or more R5, each independently) is H, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, nitro, halogen, tifluoromethyl, trifluoromethoxy or hydroxy.).),
R2 is
CONR8,
NR8CO,
CONR8xe2x80x94C1-4 alkylene,
C1-4 alkylene-CONR8,
NR8COxe2x80x94C1-4 alkylene,
C1-4 alkylene-NR8CO,
C1-3 alkylene-CONR8xe2x80x94C1-3 alkylene, or
C1-3 alkylene-NR8COxe2x80x94C1-3 alkylene
(wherein each R8 is H or C1-4 alkyl.),
O, S, NZ6 
(wherein Z6 is H or C1-4 alkyl.),
Z7-C1-4 alkylene,
C1-4 alkylene-Z7, or
C1-3 alkylene-Z7-C1-3 alkylene
(wherein each Z7 is O, S or NZ6 (wherein Z6 is as hereinbefore defined.).),
CO,
COxe2x80x94C1-4 alkylene,
C1-4 alkylene-CO,
C1-3 alkylene-COxe2x80x94C1-3 alkylene,
C2-4 alkylene,
C2-4 alkenylene, or
C2-4 alkynylene,
R3 is H, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, nitro, halogen, trifluoromethyl, trifluoromethoxy, hydroxy or hydroxymethyl,
R4 is
(1) H,
(2) C1-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl,
(3) C1-6 alkyl substituted by one or two substituent(s) selected from the group consisting of COOZ8, CONZ9Z10, and OZ8 (wherein Z8, Z9 and Z10 each, independently, is H or C1-4 alkyl.) and C1-4 alkoxy-C1-4 alkoxy,
(4) C3-7 cycloalkyl, or
(5) C1-4 alkyl, C2-4 alkenyl or C2-4 alkynyl substituted by phenyl or C3-7 cycloalkyl
(phenyl and C3-7 cycloalkyl mentioned in the above (4) and (5) may be substituted by 1-5 of R5 (wherein R5 is as hereinbefore defined.).), and n and teach, independently, is an integer of 1-4,
with the proviso that (1) R2 and Z3 should be connected at the 1- or 2-position of 
is a benzene ring and (Z2)t is other than COR1, Z1 should be connected at the 3- or 4-position of the benzene ring.), or a non-toxic salt thereof,
(2) processes for preparing them and
(3) PGE2 antagonists or agonists which comprise them as an active ingredient.